Subarachnoid hemorrhage (SAH) resulting from traumatic brain injury (TBI) can cause vasospasm, defects in cerebral blood flow (CBF) and cognitive decline. Traumatic SAH is associated with poor outcomes. The underlying causes for these injuries are unknown. Parasympathetic efferents and trigeminal afferents innervating large cerebral vessels as well as intrinsic innervation of cortical vessels may play a role in regulating CBF after injury. The present project focuses on a central neural circuit that has the potential to regulate neurovascular interactions by modulating the perivascular innervation. The objective of the proposed study is to explore a novel hypothesis, namely that the brainstem is an important mediator of cerebral perfusion during SAH. More specifically, an important medullary autonomic and sensorimotor integration center, the rostroventral medial medulla (RVM) modulates cerebral blood flow as part of a coordinated response to SAH aimed at preventing ischemia, and that failure of brainstem compensatory mechanisms contributes to the pathophysiology of subarachnoid hemorrhage. We will test three specific aims. 1. The specific neural pathways through which the RVM modulates CBF (Cetas et al., 2009) are unknown. We will test the role of parasympathetic and sympathetic outflows, interactions with trigeminal sensory pathways, and connections within the central nervous system in the effects of RVM stimulation. 2. The neurons in the RVM are diverse in terms of neurochemistry, physiology, and pharmacology. We will determine which of the physiologically defined RVM cell classes respond to SAH, and test the hypothesis that a class of neurons known to be activated by dural inflammation, ON-cells, are critical for an acute compensatory response that contributes to the restoration of CBF following an experimental SAH. 3. Determine the role of the RVM in delayed cerebral ischemia after experimental subarachnoid hemorrhage. Our overarching hypothesis in this Aim is that a failure or reorganization of RVM modulatory mechanisms is important in delayed ischemia following SAH. We will use pharmacological tools to manipulate functionally specific RVM neuronal populations. Effects of RVM manipulation on long-term outcomes will be assessed with quantitative MRI imaging and neurocognitive behavioral studies. This will allow us to test whether distinct neuronal groups in the RVM have an ongoing role in regulation of CBF in the chronic timeframe following experimental SAH. We have adapted a rodent model of SAH in which autologous blood is injected into the prechiasmatic cistern. CBF will be measured using laser Doppler and the powerful optical microangiography (OMAG). MRI will be used to supplement OMAG and correlate changes in CBF with regional isechemia and neuronal injury. We will use pharmacological tools to manipulate functionally specific RVM neuronal populations. Particular classes of RVM neurons will be indentified using standard extracellular neurophysiological recording techniques. Cognitive changes will be tested using standard learning paradigms such as the rotarod test and modified Morris water maze.